Cardiovascular disease and metabolic dysfunction-associated steatotic liver disease incidence in metabolically healthy and unhealthy normal weight obesity

BACKGROUND: Normal weight obesity (NWO) is characterized by a normal body mass index (BMI) and elevated body fat. Heterogeneous risk has been observed in people with obesity (BMI > 30) when considering metabolic risk factors (MRFs) such as high C-reactive protein, low-density lipoprotein, blood pressure, hemoglobin A1C, triglycerides, and low high-density lipoprotein. OBJECTIVES: We assessed heterogeneity between metabolically healthy (MH) and metabolically unhealthy (MU) subjects with NWO in relation to (1) incident cardiovascular disease (CVD) and metabolic dysfunction-associated steatotic liver disease (MASLD) along with (2) changes in heart physiology, liver function (assessed with imaging), and cardiometabolic/liver serum biomarkers. METHODS: In total, 121,586 subjects were classified into the following experimental groups: a healthy normal weight lean reference group ( ≤ 2 MRFs), MH-NWO ( ≤ 2 MRFs), MU-NWO ( > 2 MRFs), and people with overweight/obesity (OW/O) were classified as MH-OW/O ( ≤ 2 MRFs) or MU-OW/O ( > 2 MRFs). Primary outcomes were incident CVD and MASLD analyzed using Firth logistic regression and displayed via odds ratios (OR) and 95%-confidence intervals (95%-CI). Secondary outcomes were cross-sectional cardiac/liver imaging, serum liver enzyme, and lipid biomarkers analyzed using quantile regression. Results were deemed significant at false discovery rate (FDR) < 0.05. RESULTS: MU-NWO had higher odds of ischemic heart disease (OR 1.68, 95%-CI 1.36-2.05, FDR = 0.000007), myocardial infarction (OR 1.72, 95%-CI 1.38-2.11, FDR = 0.000007), all-cause mortality (OR 1.29, 95%-CI 1.05-1.56, FDR = 0.02), and CVD death (I0-I99); (OR 1.86, 95%-CI 1.27-2.64, FDR = 0.0036) while MH-NWO saw no significant differences. Among female subjects, both MH-NWO (OR 1.37, 95%-CI 1.04-1.78, FDR = 0.03) and MU-NWO (OR 1.78, 95%-CI 1.05-2.83, FDR = 0.03) had increased odds of MASLD. Biochemical and imaging data were consistent with enhanced CVD and MASLD risk. CONCLUSION: MRFs may modulate CVD and MASLD risk in NWO.